Humoral hypercalcemia of malignancy (HHM) and primary hyperparathyroidism (HPT) resemble one another n many ways, and these similarities have been apparent since the discovery of PTHrP in the late 1980's. On the other hand, two unresolved enigmatic differences remain between the two syndromes: HPT is associated with increases in osteoblast activity and increases in plasma 1,25(OH)2D, whereas HHM is associated with the reverse. This is surprising, because current dogma indicates that both PTH and PTHrP signal similarly via the common PTH1 receptor. Recently, we have performed directly comparative infusions of PTH and PTHrP in healthy human subjects over two to four days to evaluate the regulation of osteoblastic bone formation and 1,25(OH)2D in normal healthy subjects. These studies make surprising observations: First, in contrast to the anticipated equivalent effects on 1,25(OH)2D, steady-state, continuous infusions of PTH and PTHrP produce very different effects on 1,25(OH)2D. This suggests that the manner in which PTH and PTHrP signal via the PTH1R in human kidney is not identical. Second, despite the increase in bone formation characteristic of HPT, and despite the increase in bone formation induced by intermittent daily injections of PTH and PTHrP, 48-96 hour infusion of both PTH and PTHrP lead to marked suppression of bone formation in healthy human volunteers. These observations highlight the fact that we have much to learn about how PTH and PTHrP regulate bone formation and bone resorption. The Specific Aims of the current proposal are therefore: [unreadable] 1. To define how the temporal profile of PTH and PTHrP administration influences the anabolic skeletal response in humans [unreadable] 2. To determine how long-term continuous or pulsatile PTH and/or PTHrP influences plasma 1,25(OH)2D regulation in humans. [unreadable] These studies will be the first long-term (two week) sustained PTH or PTHrP infusion studies in humans, and are designed to elucidate the mechanisms of the mechanisms underlying the anabolic effects of PTH and PTHrP, and to fully define the apparent differences in PTH1R coupling to renal 1-alpha hydroxylase. [unreadable] [unreadable] [unreadable]